CN1265882A - 制备药物颗粒的方法 - Google Patents
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Abstract
一种制备药物颗粒的方法,该方法是使用滚压筒,在压力下将重量比例为羟氨苄青霉素:棒酸等于12∶1至1∶1的范围的羟氨苄青霉素与棒酸或其盐的结合物的药物任选地与粒内崩解剂压制成粒。
Description
本专利申请是CN92103956.5的分案申请。原申请的申请日为1992年5月6日;原申请的发明名称为“药物制剂”。
本发明关系到治疗细菌感染的口服药物制剂,以及配制这类制剂的方法。
以水分散颗粒或片剂的形式(它们可被吞咽或分散于水中后吞下)提供口服制剂是尽人皆知的。
一种已知片剂制造方法是先制备一种中间成粒剂、它含有粒内崩解剂及一种活性物质,例如抗生素。然后该粒再与粒外崩解剂(以及其它添加剂、包括润滑剂)混合并压制成片剂,此种方法,片剂和粒剂,例如已于EP0281200A,CA1199871以及JP3240023A中描述过。
人们希望此类固态制剂能很快分散浸入水中,例如通过很快使片剂崩解来达此目的。
现在披露的新的制剂能达到上述提及的所希望特性。
因此本发明提供一种含压紧颗粒结构的片状制剂,该颗粒至少含一种压紧药品,与粒内崩解剂任意结合,该颗粒再与粒外崩解剂压制在一起形成片剂,并也可任意与粒外润滑剂压在一起,如果存在润滑剂,那么润滑剂的量少于总片重的0.5%。
在本发明的片剂中,颗粒可因压制片剂而呈破碎状态,结果没有分开的边缘,或可再分或破碎成更小的颗粒。本发明也包括这类含破碎颗粒的结构。优选颗粒尺寸为100μm-2mm,适合的最大尺寸约1mm±0.25mm。
药品优选能口服吸收的,特别是β-内酰胺抗生素与β-内酰胺酶(lactamase)抑制剂的任意结合物。优选的抗生素是羟氨苄青霉素,以水合物,例如三水合物形式存在。羟氨苄青霉素可单独使用,或者任意与其它β-内酰胺抗生素和/或β-内酰胺酰(lactamase)抑制剂(例如棒酸或其盐,特别是钾盐)相结合,例如羟氨苄青霉素与之比例范围为12∶1-1∶1,比如4∶1或2∶1。优选片中抗生素比例为片总重量的60-98%,对于三水合羟氨苄青霉素来说,按三水合物的重量来计算。优选颗粒中抗生素的微粒尺寸为1μm-300μm范围,尤其是10μm-200μm。抗生素颗粒一般适合的尺寸分布是>200μ的占5%或较少,200-100μ占5-15%,100-50μ占7.5-15%<5μ的占70%或更多。
适宜的粒内崩解剂是淀粉,例如玉米淀粉和稻米淀粉,交联N-乙烯基-2-吡咯烷酮(CLPVP),淀粉乙醇酸钠,croscarmel-lose钠和甲醛-酪蛋白或其结合物。优选的粒内崩解剂是CLPVP,例如市售的商品名为Polyplasdone XL和Polyplasdone XL-10的崩解剂。
颗粒可以全含有抗生素,若是β-内酰胺抗生素可任意与β-内酰胺酶抑制剂以及粒内崩解剂结合。此外,特别是当颗粒含棒酸或其盐时,该颗粒也可含稀释剂例如硅胶(例如Syloid商标)。同抗生素一起使用的适宜的粒内崩解剂是CLPVP和淀粉乙醇酸钠。在颗粒中粒内崩解剂的一般比例是占粒重的0.1-10%,优选1.0-8.0wt%,例如1.25-3.5wt%。一般抗生素或抗生素+β-内酰胺酶抑制剂结合物在颗粒中的比例为占颗粒重量的99.9-90wt%,优选99-92wt%、例如99-95wt%,再如98.75-96.5wt%。当颗粒含稀释剂,可含高达颗粒重的30%,而与棒酸或其盐在颗粒中以1∶1的重量比存在为好。当颗粒含有稀释剂时,颗粒将相应含较低比例的抗生素或抗生素+β-内酰胺酶抑制结合物,例如含颗粒的70-99.9wt%。
抗生素和粒内崩解剂在粒中的紧密接触,有助于在与水接触时加速颗粒的崩解和分散,释放出上面优选尺寸范围的抗生素微粒,并提供极细的分散悬浮液。由于其吸水性,包括棒酸及其盐的颗粒制备随之出现一些问题,而本发明的颗粒则有助于制造。
在该片剂中颗粒的适当含量为片总重的70%或更多,例如80%或以上,90%或以上,95%或以上,以便药品在片中占高比例。
粒外崩解剂可以是常规的崩解剂,例如淀粉,比如玉米淀粉,稻米淀粉、CLPVP,淀粉乙醇酸钠,croscarmellose钠,微晶或微粒纤维素、低取代羟丙基纤维素(即以2-羟丙基基团部份取代的纤维素,例如25%以下取代、优选7-16%取代),交联羧甲基纤维素钠、可溶胀离子交换树脂,甲醛-酪蛋白或藻酸盐。优选的粒外崩解剂是CLPVP,淀粉乙醇酸钠,微粒纤维素及croscarmellose钠以及其结合物。粒外崩解剂结合的实施为微晶或微粒纤维素与淀粉乙醇酸钠,croscarmellose钠或CLPVP相结合,含80-90%重量的纤维素。
粒外崩解剂在总片重中所占比例可在很宽范围内改变,例如0.1-25%重。假如使用CLPVP或淀粉乙醇酸钠作粒外崩解剂,以片总重的0.1-5.0wt%较好,0.1-3.0wt%较适宜,优选0.1-1.5wt%。假如使用纤维素或含纤维素的结合物,例如上述含80-90%重量的纤维素,粒外崩解剂可含片总重量的1-25wt%,一般1-20wt%。
适宜的润滑剂是本技术领域常规润滑剂,例如长链脂肪酸,如硬脂酸或其盐,特别是II族金属盐例如镁或钙。
优选润滑剂是硬脂酸镁。优选润滑剂比例尽可能低些。比如0.35%重量或更低如0.275%或更少,0.25%或更少,甚至优选完全无润滑剂者。
颗粒也可含粒内润滑剂,可选择相同材料作粒外润滑剂例如硬脂酸镁。然而本发明片剂的优点是颗粒和片剂不需要含任何润滑剂。这可以促进润湿性,并因此促进片剂崩解。而且降低润滑剂比例,可使给定的抗生素剂量的片剂重量减轻。假如是可分散制剂,则可避免含较高润滑剂比例的情况下出现的“污渍”状态。
片剂也可包含常规的赋形剂,一般可含总片剂重量的约10%。这些可包括香味剂、比如薄荷醇、薄荷、香草或水果香料。一般香料剂含约总重的0.5-5%。还可含甜味剂,如aspartame,每单位剂量可含15mg左右。赋形剂也可以包括染色剂、防腐剂、悬浮助剂以及填充剂、例如二氧化硅、微晶纤维素、磷酸二钙、乳糖、山梨醇、碳酸钙或碳酸镁。优选这些赋形剂与粒外崩解剂和润滑剂(假如存在)混合在一起。存在于片中的这些材料应当是具低游离湿度,优选予干燥过的。在某些情况下,特别是当药品是抗生素,及包括棒酸或其盐时,需要加入硅胶之类的干燥稀释剂作为赋形剂。所加比例约为抗生素重量的1-5%,在粒中与抗生素和粒内崩解剂混合。赋形剂的粒度不关紧要但不能聚集成团。
该片剂中也可含已知的起泡偶合剂、例如固态酸和碱金属碳酸盐或碳酸氢盐、它们与水接触产生二氧化碳,有助于片剂崩解。
片剂可以以常规方式涂覆一层膜,比如使它好看好吃便于生产等目的,适宜的涂层包括羟丙基纤维素、丙烯酸和/或甲基丙烯酸共聚物,树脂等等。此外涂层可以是肠溶涂层,例如在酸性胃液中不溶但溶于碱性消化液的肠溶涂层。这样的涂层可使抗生素通过胃进入十二指肠,在这里被吸收。适宜的肠溶涂层包括邻苯二甲酸醋酸纤维素。因此本发明优选的成份组合物包括下表所列成份:
本发明也提供片剂制造的方法,在该片剂中其颗粒由至少一种药品,如β-内酰胺抗生素(单独)或与β-内酰胺酶(lactamase)抑制剂相结合,与粒内崩解剂紧压在一起,再与粒外崩解剂并任意与粒外润滑剂及任意与任何赋形剂相混合,假如含润滑剂则它的含量要小于整个混合物重量的0.5%,最后将该混合物压制成片。
颗粒成份 | 重量百分数 | 举 例 |
药品 | 70-99 | 羟氨苄青霉素±pot.棒酸盐 |
崩解剂 | 0.1-4 | CLPVP微晶纤维素淀粉乙醇酸钠 |
稀释剂 | 0-30 | 硅 胶 |
片剂成份 | 重量百分数 | 举 例 |
颗粒 | 70+ | 如上表所列 |
崩解剂 | 0.1-25 | CLPVP,微晶纤维素,淀粉乙醇酸钠 |
润滑剂 | 0-0.35 | 硬脂酸镁 |
赋形剂 | 到100 | 天冬酰苯丙氨酸甲酯,香味剂着色剂,二氧化硅 |
适宜的和优选的抗生素,粒内和粒外崩解剂、润滑剂、赋形剂、颗粒和粒度以及其相对比例如上所述。
本发明的方法所需的颗粒可以按下述方法制得:将粉末形式的药品与干燥的粒内崩解剂混合,并于压力下将混合物压紧。就此制备方法而论,使用粒内崩解剂CLPVP,淀粉乙醇酸钠、酪蛋白-甲醛、croscarmellose钠或其结合物这一构思,相信是具有新颖性的,它是本发明的另一方面。
在该方法中,需要将抗生素碾磨和过筛使其具所需粒度范围。也需要将粒内崩解剂碾磨和过筛到适当的粒度,例如对于CLPVP而言约30μ,但粒度并不至关重要。
压紧混合物成粒可以采用常规的干压法,例如压、滚、挤等等,为压制加工适宜的压力是30-200KN,例如35-65KN优选40-50KN。上述颗粒制剂特别适于由滚筒压制成型。压紧以后,还需要碾磨和过筛压紧的混合物,以便达到适宜的颗粒尺寸分布。压制成片可采用常规方法进行,例如用常规的压片机。作为另一个任意步骤,可如上所述将该片剂涂以涂层。
当上述颗粒含药品为β-内酰胺抗生素(例如羟氨苄青霉素)与β-内酰胺酶(lactamase)抑制剂(例如clavulanic酸或其盐,特别是其钾盐)相结合时,认为这些颗粒具新颖性,这是本发明的又一个方面。这些颗粒的适宜和优选性质如上所述。
除了片剂外,上述颗粒还可适用于制备其它药物制剂,例如它们还可作为含适当单位剂量的香粉形式,作为可自由流动的粒剂施用。它们也可以与赋形剂(例如甜味剂、增稠剂、防腐剂)和缓冲剂(例如苯甲酸钠,乙酸钠和柠檬酸钠)一起溶解在水中,形成糖浆制剂,例如供小孩服用。
颗粒能形成一种松散的压制品,能在与水接触时很快分散使得它们特别适宜用于胶囊剂。因此,本发明的另一方面是提供含这种颗粒的胶囊制剂。此种胶囊制剂可任意包括粒外润滑剂,如果其存在,其适宜含量为颗粒重量的0.5%以下,包含在一种药物的胶囊中。
优选的药品为能口服吸收的,特别是任意与β-内酰胺酶(lac-tamase)抑制剂结合的β-内酰胺抗生素。对胶囊制剂来说适宜的优选抗生素,β-内酰胺酶(lactamase)抑制剂、粒内崩解剂、粒外润滑剂、颗粒、粒度以及其相对比例正如上面所述,此外,优选润滑剂比例是粒重的0.1-0.5%,特别是0.32-0.35%。
药物胶囊可以是完全常规的胶囊例如明胶制成的,能在胃中溶解释放出内容物。
上述药物制剂优选含有单位抗生素剂量者,例如含375、500、750或1000mg羟氨苄青霉素(每片或每个胶囊)。该药片也可在咽下以前分散于水中,或者也可以咀嚼或整个吞下去。
本发明进一步提供上述药物制剂,作为活性治疗物质使用。
本发明进一步提供上述药物制剂,其中药品是β-内酰胺抗生素任意与β-内酰胺酶(lactamase)抑制剂相结合,用于治疗细菌感染。
本发明进一步提供如上所述的药物制剂的使用方法,其中在药物制造中药品是β-内酰胺抗生素任意与β-内酰胺酶(lactamase)抑制剂结合,用于治疗细菌感染。
本发明进一步提供治疗哺乳动物细菌感染的方法、包括给哺乳动物施用有效量的如上所述的药物制剂,其中药品是β-内酰胺抗生素任意与β-内酰胺酶抑制剂相结合。
现仅以实施例的方式对本发明加以说明。
例1:成粒
将羟氨苄青霉素三水合物磨细,用0.04或0.027英时(1.0-0.7mm)筛孔过筛,在混合器中与干燥的交联聚乙烯吡咯烷酮(分子量约1百万,密度为1.22mg/cm3,PolyplasdoneXL-Trade Mark)混合15分钟,混合物含3.4%重量的CLPVP。
使用滚筒压制器,控制压力在50KN,将该混合物压在一起,压制的片状物用碾磨器使之成粒,或者通过装有1mm筛眼的筛将之成粒获得适宜的尺寸分布。
例2:制片
按如下组成制片:
为制备这些片剂,将干燥的淀粉乙醇酸钠,硬脂酸镁和微晶纤维素过筛,然后与实施例1中的颗粒混合。然后加入天冬酰苯丙氨酸甲酯,将混合物混合至均匀(5分钟)。最后用常规压片机将混合物压制成片。
例3:成粒
用例1的方法制粒,含97wt%的三水合羟氨苄青霉素及3wt%的polyplasdone XL控制压力为40-50KN。
例4:制片
按如下组成制片
成份 wt.mg wt.mg wt.mg wt.mg wt.%羟氨苄青霉素 375 500 750 1000 83.001CLPVP 17.5 23.33 35 46.65 3.782薄荷 3 4 6 7.99 0.65干香料天冬酰苯丙氨 7.5 10 15 19.99 1.62酸甲酯硬脂酸镁 1 1.34 2 2.67 0.21
(1)相当于三水合羟氨苄青霉素的95wt%。
(2)3%为粒内崩解剂,而0.78%粒外崩解剂。
为制片,将干燥的香料、aspartame、硬脂酸镁和相当混合物总重0.78wt%的CLPVP(polyplasdone XL)按上表所示重量百分比与例3的颗粒混合5分钟。用常规压片机将该混合物压成片。
本例的含750mg羟氨苄青霉素(三水合物)的一般片剂具下述特性:
重量: 925mg±5%
硬度: >16KP
水中分散时间: <1分钟
易碎性 <1%
表象 卵形17×10×7mm片
例5:成粒
采用与例1相同的方法制粒,将97.12wt%三水合羟氨苄青霉素与2.88wt%淀粉乙醇酸钠(即Primogel,作为粒内崩解剂)压在一起。
例6:制片
按如下组成制片
成份 重量mg. 重量%(Avicel PH102)
(1)相当于游离酸
为制片,用1mm筛将例5的颗粒过筛,然后与适当量的硬脂酸镁(润滑剂)和微晶纤维素混合(混合15分钟)。然后将混合物压制成具如下特性的片:
重量: 950mg
硬度: 12-16KP
水中分散时间: 10-15秒(37℃)
20-25秒(20℃)
该片可以以如上所述的未涂覆状态分散于水中然后吞服,或可涂膜后吞服。
例7:胶囊制剂
例3的颗粒可以同占总重0.34%的硬脂酸镁润滑剂在较轻压力下压制成松散的压制品。该松散的压制品被封于明胶胶囊中,含如下的混合物:
成份 重量mg. 重量%
三水合羟氨苄青霉素: 573.911 96.8
CLPVP: 17 2.9
硬脂酸镁: 2 0.34
(1)相当于500mg羟氨苄青霉素游离酸。
例8:香粉剂
按例1的方式制粒,即碾磨和过筛成粒成份,接着用滚筒压制(50KN)成粒。该颗粒可制成适于加工带粒外赋形剂的香粉表型的混合物。
本例的颗粒可按适当羟氨苄青霉素/棒酸盐重量比以:香粉态施用,也适于制成糖浆制剂。例如所列重量可以配成60ml的156.25mg/5ml的糖浆,或者两倍所列重量配成60ml浆液制得312.5mg/5ml糖浆。这些糖浆不含外加的糖。
例9:成粒
成份 重量mg. 重量%
(1)相当于500mg羟氨苄青霉素游离酸
(2)相当于125mg游离棒酸
采用与例8相同的方式将该混合物制粒。这些颗粒适于以香粉施用,混入香料和蔗糖,对于上面所列每剂香粉的颗粒量来说,按下表所列比例掺入之:
柠檬干香料 136.0mg
草霉干香料 44.0mg
桃干香料 34.0mg
蔗糖 直到3500mg
含有其它重量羟氨苄青霉素的香粉,例如含250或125mg,也可按所列重量比来制约,并可用蔗糖补充到1750mg总重量。
例10:制片
成份 重量mg. 重量%
(1)相当于500mg羟氨苄青霉素游离酸。
(2)相当于125mg游离棒酸
使用与例8相同的方式制粒。将香料、polyplasdone XL、着色剂和硬脂酸镁过筛后与颗粒混合,然后加入天冬酰苯丙氨酸甲酯,尔后在常规压片机上将该混合物压制成片。该片含625.0mg的羟氨苄青霉素和棒酸盐的结合物,且所用量可以减半制成含312.5mg的片。
例11:制片
(1)相当于250mg羟氨苄青霉素游离酸。
(2)相当于125mg游离棒酸。
使用与实施例10相同的方法用该混合物制片。
例12:香粉或糖浆制剂
成 份 重量mg. 重量%
羟氨苄青霉素:棒酸钾
粒12255.6 63.34∶1 W∶W+3wt% CLPVP
CLPVP 13.5 0.38
柠檬干香料 408.0 11.46
草霉干香料 132.0 3.71
桃干香料 102.0 2.86
二氧化硅USNF(Syloid AL-1) 450.0 12.64
天冬酰苯丙氨酸甲酯 45.0 1.26
黄原胶 150.0 4.21
总重 3561.6 100.0
(1)羟氨苄青霉素:Clav表示游离酸
使用实施例8的方法制粒。此种制剂可以以香粉施用,或可制成糖浆,例如浓度为3561.6mg/60ml或7123.2mg/60ml(分别等于156.25和312.5mg羟氨苄青霉素:棒酸盐/5ml)为将糖浆调节到适当粘度和pH,可使用aerosil 200(一种高度分散的硅胶),琥珀酸和/或methocel E-15(干)。
例13:香粉制剂
成份 重量mg. 重量%
颗粒(羟氨苄青霉素:Kclav
4∶1或7∶1+3%PVP) 500 250 125 875 7-25
柠檬干香粉 136 68 34 136)
草莓干香粉 44 22 11 44) 3-6.1
桃干香粉 34 17 8.5 34)
二氧化硅U.S.N.F 150 75 37.5 150 2.1-4.3
(Syloid AL-1)
- - - - -
蔗 糖 到 3500 1750 1750 3500 到100
(1)重量和羟氨苄青霉素/Kclav均表示游离酸。
使用实施例8的方法制粒,然后再与其它赋形剂混合。
例14:片剂
羟氨苄:Clav1 4∶1 4∶1 2∶1 7∶1
成份 重量mg. 重量%
颗粒2 751.9 376.0 452.1 1201.3 70.90
干香料3 6.0 3.0 3.0 8.0 0.48-0.63干Poliplasdone XL100.0 50.0 66.5 110.1 8.1-10.7
天冬酰苯丙氨酸甲酯 15.0 7.5 7.5 15.0 1.1-1.6
着色剂 4-5 2-2.5 2-2.5 4-5 0.3-0.55
硬脂酸镁 2.5 1.25 1.25 3.4 0.19-0.26
二氧化硅
- - - - - -
(Syloid AL-1)到 950 475 628 1350 到100
(1)羟氨苄:Clav表示羟氨苄青霉素的重量与棒酸盐游离酸的重量比。
(2)颗粒=羟氨苄:Clav+3% CLPVP
(3)薄荷或中国柑桔。
使用例9的方法制粒。
使用实施例9的方法制粒,除天冬酰苯丙氨酸甲酯外将其它的赋形剂过筛和混合,然后与颗粒混合,再加入天冬酰苯丙氨酸甲酯,最后用常规区片机将混合物压制成片。该片含625mg的羟氨苄青霉素:棒酸盐相混合。可配制成不同活性强度的片剂、例如含1000,375或312.5mg羟氨苄青霉素:棒酸盐结合物。
例15:片剂
有机涂覆膜 有 有 有 有 到100
实际重量 1050.0 - - 1450.0
(1)羟氨苄:Clav表示游离酸。
按实施例14相同的方法制片。
例1-15的成份的相对比例和重量,均可围绕表中所列数字作某些改变,但较为适宜的是按表所列增减10%范围,希望±5%以内,尤其是±2.5%以内。
Claims (4)
1.一种制备药物颗粒的方法,该方法是使用滚压筒,在压力下将重量比例为羟氨苄青霉素∶棒酸等于12∶1至1∶1的范围的羟氨苄青霉素与棒酸或其盐的结合物的药物任选地与粒内崩解剂压制成粒。
2.根据权利要求1的方法,其中崩解剂选自玉米淀粉、交联N-乙烯基-2-吡咯烷酮、淀粉乙醇酸钠、交联羧甲基纤维素钠、甲醛-酪蛋白或其结合物。
3.根据权利要求2的方法,其中粒内崩解剂的比例占制剂的0.1-10wt%。
4.根据权利要求1的方法,其中颗粒含有羟氨苄青霉素加上棒酸或其盐相结合的药品、交联N-乙烯基-2-吡咯烷酮或淀粉乙醇酸钠粒内崩解剂,以及任意一种或多种稀释剂,其配比为70-99wt%药品,0.1-5wt%崩解剂及直到30wt%的稀释剂。
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